Decahydroquinolines and 5,6,7,8 tetrahydroquinolines

ABSTRACT

A compound selected from the group consisting of all enantiomeric and diastereoisomeric forms of a decahydroquinoline of the formula ##STR1## wherein R 1  is alkyl of 1 to 5 carbon atoms, R 2  is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms, A is selected from the group consisting of --(CH 2 ) n  --, --CH 2  O-- and alkylene substituted with alkyl having a total of 2 to 8 carbon atoms, n is an integer from 0 to 5, Z is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted indenyl, optionally substituted heteromonocycle of 5 to 6 members and optionally substituted heterobicycle with the proviso that when Z is o-alkoxy-phenyl, A is not --(CH 2 ) n  -- in which n is O, and their non-toxic, pharmaceutically acceptable acid addition salts and their quaternary ammonium salts and intermediates having analgesic, diuretic, hypotensive, anti-arrithmic and anti-cerebral-ischaemic properties.

This a division of Ser. No. 084,456 filed Aug. 12, 1987, U.S. Pat. No.4,877,796.

STATE OF THE ART

Related prior art are Journal of Med. Chem., Vol. 25, Oct. 1982, p.1125-1126 and Vol. 17, Nov. 1974, p. 1136-1139 and copending U.S. patentapplication Ser. No. 002,778 filed Jan. 13, 1987.

OBJECT OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and quaternary ammonium salts and a process and intermediates fortheir preparation.

It is another object of the invention to provide novel central analgesiccompositions and a novel method of inducing central analgesic activityin warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of all enantiomeric and diastereomeric forms of adecahydroquinoline of the formula ##STR2## wherein R₁ is alkyl of 1 to 5carbon atoms, R₂ is selected from the group consisting of hydrogen andalkyl of 1 to 5 carbon atoms, A is selected from the group consisting of--(CH₂)_(n) --, --CH₂ O-- and alkylene substituted with alkyl having atotal of 2 to 8 carbon atoms, n is an integer from 0 to 5, Z is selectedfrom the group consisting of optionally substituted phenyl, optionallysubstituted naphthyl, optionally substituted indenyl, optionallysubstituted heteromonocycle of 5 to 6 members and optionally substitutedheterobicycle with the proviso that when Z is α-alkoxy-phenyl, A is not--(CH₂)_(n) -- in which n is 0, and their non-toxic, pharmaceuticallyacceptable acid addition salts and their quaternary ammonium salts.

Examples of substituents when Z is phenyl are alkyl and alkoxy of 1 to 5carbon atoms, halogen, --OH, --CF₃, --NO₂, --NH₂ and mono anddialkylamino of 1 to 5 alkyl carbon atoms. Examples of substitutentswhen Z is naphthyl, indenyl or heterocycle are alkyl and alkoxy of 1 to5 carbon atoms, --CF₃, --NO₂, --NH₂ mono- and dialkylamino of 1 to 5alkyl carbon atoms and phenyl optionally substituted with one or moremembers of the group consisting of alkyl and alkoxy of 1 to 5 carbonatoms and halogen.

Examples of alkyl and alkoxy of 1 to 5 carbon atoms are methyl, ethyl,isopropyl, n-propyl, butyl, methoxy, ethoxy, isopropoxy, n-propoxy andbutoxy. Examples of halogen are fluorine, bromine, chlorine and iodine.The mono- and dialkylamino preferably have methyl or ethyl as the alkyl.

Examples of Z as a heteromonocycle of 5 to 6 members are thiazolyl,pyridinyl, oxazolyl, isoxazolyl, imidazolyl and thienyl and examples ofZ as a heterobicycle are indolyl, quinolyl, benzo[b]thienyl,benzimidazolyl, benzoxazolyl and benzothiazolyl.

When A is --(CH₂)_(n) --, n is preferably 0 or 1. When A is alkylenesubstituted by alkyl, the alkyl is preferably methyl or ethyl andspecific examples are 1,1-ethanediyl, 1-methyl-1,2-ethanediyl,1-methyl-1,3-propanediyl, 2-methyl-1,3-propanediyl and1-ethyl-1,2-ethanediyl.

The compounds of formula I can exist in the form of four racemates orpairs of enantiomers which pairs can be separated by known procedures.The invention relates to all enantiomeric and diasteroisomeric forms.

Examples of suitable acids for the non-toxic, pharmaceuticallyacceptable acid addition salts are inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acidand organic acids such as formic acid, acetic acid, propionic acid,maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid,oxalic acid, glyoxylic acid and aspartic acid, alkane sulfonic acidssuch as methane sulfonic acid, arylsulfonic acids such as benzenesulfonic acid and arylcarboxylic acids such as benzoic acid.

Examples of quaternary ammonium salts are the compounds of formula Iquaternized with an R-Y compound in which R is alkyl of 1 to 4 carbonatoms such as methyl, ethyl, isopropyl and n-propyl and Y is a halidesuch as chloride, bromide or iodide.

Among the preferred compounds of formula I are those wherein R₁ is alkylof 1 to 5 carbon atoms, A is a linear --(CH₂)_(n) --, n is a wholenumber from 0 to 5 or a branched alkylene of 2 to 8 carbon atoms, R₂ ishydrogen or alkyl of 1 to 5 carbon atoms, Z is phenyl substituted by Xand X' which are individually hydrogen, alkyl and alkoxy of 1 or 4carbon atoms, --OH, halogen, --CF₃, --NO₂, --NH₂ and mono- anddialkylamino with the proviso that when X or X' is o-alkoxy on thephenyl and A is --(CH₂)_(n) --, n is not 0 and their acid addition andquaternary ammonium salts in all possible enantiomeric anddiastereoisomeric forms.

The preferred compounds of formula I are those wherein the junction ofthe rings is cis and those wherein A is --CH₂ -- or --CH₂ O-- and theirnon-toxid, pharmaceutically acceptable acid addition salts.

A particular preferred group of compounds are those wherein R₁ is methylor ethyl, R₂ is hydrogen, methyl or ethyl and Z is phenyl optionallysubstituted with 1 or 2 members of the group consisting of methyl,ethyl, methoxy, ethoxy, chlorine, bromine, --CF₃ and --NO₂ and thosewherein R₁ is methyl or ethyl, R₂ is hydrogen, methyl or ethyl and Z isnaphthyl, pyridinyl or benzo[b] thienyl and their non-toxic,pharmaceutically acceptable acid addition salts.

Specific preferred compounds of the invention are [4aRS (4aα,8α, 8aα,)](±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamideand (4aα, 8α, 8aα) (±)N-(decahydro-1-methyl-8-quinolinyl)-[2-(3,4-dichlorophenoxy)]N-methyl-acetamideand their non-toxic, pharmaceutically acceptable acid addition salts.

The novel process of the invention for the preparation of compounds offormula I comprises reacting 8-chloro-5,6,7,8-tetrahydroquinoline with acompound of the formula X--R₁ wherein R₁ is alkyl of 1 to 5 carbon atomsand X is halogen to obtain a compound of the formula ##STR3## reactingthe latter with an amine of the formula R₂ -NH₂ wherein R₂ is hydrogenor alkyl of 1 to 5 carbon atoms to obtain a compound of the formula##STR4## reducing the latter to obtain a product of the formula in allthe possible enantiomeric and diastereoisomeric forms: ##STR5## andcondensing the latter with an acid of the formula or a functionalderivative thereof:

    HOOC--(A)--Z                                               V

A and Z have the above definitions to obtain a product of formula I inall the possible enantiomeric and diastereoisomeric forms, which can beresolved to obtain the optically active forms and which are treated ifdesired, with a mineral or organic acid to form the acid addition salts.

Preferably, X--R₁ is an alkyl halide and the reaction is effected inacetonitrile. The reduction of the compounds of formula III is effectedby catalytic hydrogenation in the presence of platinum oxide. Thecarboxyl group of the compound of formula V is activated in the presenceof carbonyldiimidazole or dicyclohexylcarbondiimide and the compound offormula V is preferably the acid chloride or mixed anhydride.

The two isomers of the compounds of formula IV have the --NH--R₂ groupin the α- or β- orientation with respect to the ring and can beseparated by chromatography. The racemates may be separated as salts ofthe diastereoisomers with optically active acids.

The compounds with the formula (I) as defined above as well as theiraddition salts with acids show useful pharmacological properties. Theyshow in particular a stron affinity for the opiate receptors and inparticular for the K receptors and are endowed with central analgesicproperties.

They are also endowed with diuretic properties, and anti-arrythmicanti-cerebral-ischaemic and hypotensive properties.

The subject matter of the invention is also the novel central analgesiccomposition which comprised at least one compound of formula I and itsnon-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts and an inert pharmaceutical carrier orexcipient.

The compositions are useful for alleviating pain of any origin such asmuscular, articular or nevous nature.

They can be used in the treatment of dental pains or migraines,shingles, in the treatment of severe pains, in particular thoserefractory to peripheral antalgesics, for example during neoplasticprocess, in the treatment of pancreatitis, renal or biliary colic, inthe treatment of post-operation and post-traumatic pains.

The subject matter of the invention is also the novel diurecticcompositions which comprise at least one compound of formula I and itsnon-toxi pharmaceutically acceptable acid and addition salts andquaternary ammonium salts and an inert pharmaceutical carrier orexcipient.

The compositions can be used in the treatment of oedemato syndrones, ofcardiac insufficiency, of certain obesities, of cirrhoses, in thetreatment of severe refractory oedemas, in particular those ofcongestive cardiac insufficiency and in the lengthy treatment ofarterial hypertension.

The subject matter of the invention is also the novel antiarrythmiccompositions which comprise at least one compound of formula I and itsnon-toxi pharmaceutically acceptable acid addition salts and quaternaryammonium salts and an inert pharceutical carrier or excipient.

The compositions can be used in the treatment of ventricular,supraventricular and functional arrythmias. The compositions may be inthe form of tablets, dragees, gelules, granules, suppositories, creams,ointments, gels, aerosols and injectable solutions or suspensions.

Examples of suitble excipients are talc, gum arabic, lactose, starch,magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting, dispersing or emulsifying agents and preservatives.

The novel method of relieving pain in warm-blooded animals includinghumans, comprises administering to warm-blooded animals a centralanalgesically effective amount of at least one compound of formula I andits non-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts. The compounds may be administred orally,rectally or parenterally and the usual daily dose is 0.05 to 6 mg/kgdepending on the condition treated, the specific compound and method ofadministration. For example, a daily oral dose of 0.2 to 6 mg/kg isuseful for analgesic activity.

The novel method of inducing diuresis in warm-blooded animals includinghumans, comprises administering to warm-blooded animals a diureticallyeffective amount of at least one compound of formula I and itsnon-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts. The compound may be administered orallyrectally or parenterally and the usual daily dose is 1γ to 1 mg/kgdepending on the condition treated, the specific compound and method ofadministration. For example a daily oral dose of λoγ to 1 mg and a dailyparenteral dose of 1γ to 100γ kg are useful for diuretic activity, moreparticularly a daily oral dose of 10γ to 100γ/kg and a daily parenteraldose 5γ to 50γ/kg.

The novel method of treating arrythmia in warm blooded animals includinghumans, comprises administering to warm blooded animals aantiarythmically effective amount of at least one compound of formula Iand its non-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts. The compounds may be administered preferablyorally, rectally or parenterally and the usual daily dose is 3 to 12mg/kg depending on the condition treated, the specific compound andmethod of administration.

The compounds of formulae III and IV are novel intermediates and8-chloro-5,6,7,8-tetrahydroquinoline starting material may be obtainedby the process of U.S. Pat. No. 3,991,065 by chlorination of5,6,7,8-tetrahydroquinoline-N-oxide.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1 [4aRS (4aα, 8α, 8aα)] (±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamideSTEP A: 8-iodo-1-methyl-5,6,7,8-tetrahydro-1-quinolinium iodide

A solution of 13.70 g of 5,6,7,8-tetrahydro-8-chloroquinoline(preparation given below), 86 ml of acetonitrile and 15.2 ml of methyliodide was stirred for 68 hours at ambient temperature andcrystallization was started after 50 minutes of reaction. The crystalswere separated, rinsed with acetonitrile, then with ether and driedunder reduced pressure at 20° C. to obtain 29.96 g of8-iodo-1-methyl-5,6,7,8-tetrahydro-1-quinolinium iodide melting at 175°C.

Preparation of 5,6,7,8-tetrahydro-8-chloroquinoline

3 ml of methane sulfonyl chloride were slowly added at ambienttemperature to 1.49 g of 5,6,7,8-tetrahydroquinoline N-oxide withstirring under an inert atmosphere and the mixture was then heated for 4hours at 80°-82° C. and then cooled to 20° C. The mixture was pouredinto 20 ml of a saturated solution of sodium bicarbonate and then sodiumbicarbonate was added slowly until an alkaline pH was obtained.Extraction was carried out with methylene chloride and the extracts werewashed with water. The combined organic solutions were dried anddistilled to dryness to obtain 1.53 g of8-iodo-1-methyl-5,6,7,8-tetrahydro-1-quinolinium iodide in the form ofan oil.

STEP B: 1-methyl-8-(methylamino)-5,6,7,8-tetrahydro-1-quinolinium iodide

8.02 g of the product of step A were introduced into 40 ml oftetrahydrofuran and then 7.4 ml of an ethanol solution of monoethylaminewas added all at once with a pipette. The suspension was stirred for 20hours at ambient temperature and the crystals were separated, rinsedwith tetrahydrofuran and ether and dried under reduced pressure at 20°C. to obtain 4.76 g of1-methyl-8-(methylamino-5,6,7,8-tetrahydro-1-quinolinium iodide meltingat 180° C.

STEP C: [4aRS (4aα, 8α, 8aα] (±) decahydro-N, 1-dimethyl-8-quinolinamineand [1aRS (4aα, 8α, 8aα)] (±) decahydro-N, 1-dimethyl-8-quinolinamine

1.029 g of platinum oxide were added all at once to a solution of 10.29g of the product of Step B in 150 ml of acetic acid and the suspensionwas hydrogenated at 22° to 24° C. for 50 hours. After 29 hours ofhydrogenation, 1 g more of platinum oxide was added and at the end ofthe reaction, 30 ml of water were added. After filtering, rinsing withmethanol and distilling under reduced pressure, the residue was taken upin 200 ml of ether. 200 ml of sodium hydroxide solution diluted to onehalf were added slowly with stirring and cooling. After stirring anddecanting, the aqueous phase was extracted with ether and the organicphases were dried and distilled under reduced pressure to obtain 5.60 gof [4aRS (4α, 8α, 8aα,] (±) decahydro-N,1-dimethyl-8-quinolinamine and[4aRS (4aα, 8α, 8aα,)] (±) decahydro-N,1-dimethyl-8-quinolinamine whichwas a mixture of the 2 diastereoisomers at the junction of the cis ring.

Separation of the 2 diastereoisomers by preparative chromatography

A preparative chromatography was carried out on silica (eluent: ethylacetate-methanol-triethylamine 85-10-5) at atmospheric pressure. It wasleft in contact with the eluent for one hour and 5.5 g of crude basewere chromatographed. A fraction of 579 mg of a mixture of 3 mobileproducts was recovered first and then the fractions corresponding to theisomer having 8α- orientation were brought to dryness under reducedpressure. 1.122 g of product with 8α- orientation were obtained. Thefractions corresponding to the isomer having 8β- orientation werebrought to dryness under reduced pressure. 3.361 g of product with 8β-orientation were obtained.

STEP D: [4aRS (4aα, 8α, 8aα)] (±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamideand its hydrochloride

2.13 g of 3,4-dichlorophenyl acetic acid, 1.69 g of carbonyldiimidazoleand 20 ml of tetrahydrofuran were stirred at 20° C. for 1 hour and then1.46 g of 8α-diastereoisomer obtained in Step C in solution in 5 ml oftetrahydrofuran were added with stirring for 3 hours and 30 minutes at20° to 22° C. The tetrahydrofuran was eliminated under reduced pressureand the residue was taken up by 50 ml of ether, washed with a saturatedsolution of sodium bicarbonate, then with salted water, dried, rinsedand concentrated under reduced pressure to obtain 3.73 g of crudeproduct. The latter was purified by passage through oxalate and 3.645 gof crude product were dissolved in 10 ml of ethanol. 1.5 g of oxalicacid in solution in 2.5 ml of ethanol were added and the insolubleproduct was filtered off, rinsed with ethanol and dried under reducedpressure at 20° C. to obtain 464 mg of product. 120 ml of ether wereadded slowly to the mother liquors and a gum precipitated. Thesupernatant solution was decanted and rinsed with ether and the gum wastaken up in water and made alkaline with sodium bicarbonate in thepressure of 50 ml of ether. After decanting, washing with salted water,drying and concentrating to dryness under reduced pressure, 2.29 g of[4aRS 4α, 8α, 8aα)] (±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamidewere obtained in the form of an oily dry extract which crystallized andmelting at 92° C.

Preparation of the hydrochloride

2.15 g of dry extract were dissolved in 5 ml of ethanol at 50° to 60° C.and after filtering, the filtrate was rinsed with ethanol and withether. 2 ml of hydrochloric acid in ethanol were added andcrystallization was started. A thick mass formed which was diluted withether, separated, rinsed with ethanol, and an ether ethanol mixture(3-2) and then with ether. Drying under reduced pressure at 70° C.yielded 2.05 g of [4aRS 4α, 8α, 8aα)] (±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamidehydrochloride melting at 253° C.

EXAMPLE 2 [4aRS (4aα, 8α, 8aα)] (±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamide

1.46 g of dicyclohexylcarbondiimide were introduced into a solution of1.46 g of 3,4-dichlorophenylacetic acid, 1.222 g of 8β-diastereoisomerobtained in Step C of Example 1 and 20 ml of methylene chloride and themixture was stirred for 3 hours and 30 minutes, then filtered and rinsedwith methylene chloride. The filtrate was concentrated to dryness underreduced pressure and the residue was taken up in ether, washed with asaturated aqueous solution of sodium bicarbonate, then with saltedwater, dried and concentrated to dryness under reduced pressure toobtain 2.845 g of product. The latter was taken up in 15 ml of ether andcrystallization was started. The crystals were dried, rinsed with etherand dried under reduced pressure to obtain 2.053 g of product. 1.885 gof the product was purified by chromatography on silica (eluent: ethylacetate with 2% of triethylamine) and the homogeneous fraction wasevaporated to dryness to obtain 1.477 g of product which were dissolvedin methylene chloride and filtered. The methylene chloride was distilledoff under reduced pressure while introducing isopropyl ether. Theproduct crystallized during distillation and the crystals wereseparated, rinsed with isopropyl ether, dried under reduced pressure at50° C. to obtain 1.27 g of [4aRS (4aα, 8α, 8aα)] (±)N-(deecahydro-1-methyl-8-quinolinyl)-3,4-dichloro-N-methyl-benzene-acetamidemelting at 139° C.

Preparation of the hydrochloride

1.2 g of the product were dissolved in 4.8 ml of ethanol and 1 ml ofethanol containing hydrochloric acid (5.75N) at 20° C. The solution wasfiltered and the filtrate was rinsed with ethanol and concentrated todryness under reduced pressure. The residue was triturated in 10 ml ofether, separated, rinsed with ether and dried under reduced pressure at70° C. to obtain 1.259 g of the hydrochloride melting at 258° C.

Using the procedure of Example 1, [4aRS (4aα, 8α, 8aα)] (±)decahydro-N,1-dimethyl-8-quinolinamine and a suitable acid were reactedto obtain the products of Examples 3 to 11.

EXAMPLE 3

[4aα, 8α, 8aα,] (±)N-(decahydro-1-methyl-8-quinolinyl)-N-methyl-4-nitrobenzene-acetamideand its hydrochloride.

EXAMPLE 4

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quinolinyl)-N-methyl-4-(trifluoromethyl)-benzene-acetamideand its E-butene dioate.

EXAMPLE 5

[4aα, 8α, 8aα]4-bromo-N-(decahydro-1-methyl-8-quinolinyl)-N-methyl-benzene-acetamideand its hydrochloride.

EXAMPLE 6

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quinolinyl)-4,N-dimethyl-benzene-acetamide andits hydrochloride.

EXAMPLE 7

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quinolinyl)-2-(3,4-dichlorophenoxy)-N-methylacetamideand its E-butene dioate.

EXAMPLE 8

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quinolinyl)-3,4-dimethoxy-N-methyl-benzene-acetamideand its E-butene dioate.

EXAMPLE 9

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quinolinyl)-N-methyl-1-naphthalene-acetamide andits E-butene dioate.

EXAMPLE 10

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quniolinyl)-N-methyl-4-pyridine-acetamide andits oxalate.

EXAMPLE 11

[4aα, 8α, 8aα] (±)N-(decahydro-1-methyl-8-quinolinyl)-N-methyl-benzo(b)thiophene-acetamide.

The acid used, the results of the analysis and the melting points of theproducts obtained appear in Table I hereafter.

                                      TABLE I                                     __________________________________________________________________________                        Microanalysis: Calculated/Found                           Example                                                                            Acid used at the start                                                                       C %                                                                              H %                                                                              N %                                                                              Cl %                                                                              Br %                                                                              S %                                                                              M.P. (°C.)                     __________________________________________________________________________    3    p-nitrophenyl acetic acid                                                                    59.75                                                                            7.39                                                                             11.00                                                                            9.28       #228.sup.                                                 59.6                                                                             7.3                                                                              10.8                                                                             9.4        (decomp)                              4    p-trifluoromethyl acetic acid                                                                59.49                                                                            6.45                                                                             5.78                                                                             11.76      180                                                       59.7                                                                             6.77                                                                             5.7                                                                              11.45                                            5    p-bromophenyl acetic acid                                                                    54.88                                                                            6.79                                                                             6.74                                                                             8.52                                                                              19.22  >260                                                      54.6                                                                             6.9                                                                              6.5                                                                              8.2 19.0                                         6    p-tolyl acetic acid                                                                          68.45                                                                            8.90                                                                             7.98                                                                             10.10      >260                                                      68.4                                                                             9.2                                                                              7.8                                                                              10.3                                             7    3,4-dichlorophenoxy acetic acid                                                              55.09                                                                            6.03                                                                             5.59                                                                             14.14      205                                                       55.1                                                                             6.1                                                                              5.5                                                                              14.0                                             8    3,4-dimethoxyphenyl acetic acid                                                              63.01                                                                            7.61                                                                             5.88          #150.sup.                                                 63.1                                                                             7.7                                                                              5.6           (decomp)                              9    1-naphthyl acetic acid                                                                       69.50                                                                            7.34                                                                             6.00          199                                                       69.6                                                                             7.4                                                                              6.0           (decomp)                              10   4-pyridyl acetic acid                                                                        54.88                                                                            6.49                                                                             8.73          187                                                       54.6                                                                             6.4                                                                              8.7                                                 11   4-thianaphthene acetic acid                                                                  64.18                                                                            7.44                                                                             7.13                                                                             9.02    8.16                                                                             >260                                                      63.9                                                                             7.4                                                                              7.2                                                                              9.3     8.0                                      __________________________________________________________________________

EXAMPLE 12

Tablets were prepared containing 200 mg of product of Example 1 andsufficient excipient of lactose, talc, starch and magnesium stearate fora final tablet weight of 800 mg.

EXAMPLE 13

An injectable solution (intra-muscular route) was prepared containing 50mg of the product of Example 7 and sterile solvent for a volume of 5 ml.

PHARMACOLOGICAL STUDY A. Bond to the optiated K receptor in vitro

Membrane residues were used preserved at -30° C. (possibly for about 30days) and prepared from guinea pigs brains. The residues were put intosuspension in a buffer Tris pH 7.7 and 2 ml fractions were distributedin haemolysis tubes. 9³ H ethylketocyclazocine 1 nM was added as well asthe test product. The product was first tested at 5×10⁻⁶ M (intriplicate). When the product tested displaced the radioactivity linkedspecifically to the receptor by more than 50%, it was tested again in arange of 7 doses to determine the dose which inhibits by 50% theradioactivity linked specifically to the receptor to determine the 50%inhibiting concentration. The non-specific link was determined byaddition of a porduct called U-50488 H (Lahti et al 1982, Life Sci. Vo.31, 2257) at 10⁻⁵ M in triplicate. It was incubated at 25° C. for 40minutes and held in a water bath at 0° C. for 5 minutes, filtered undervacuum, rinsed with a buffer Tris pH 7.7 and the radioactivity wascounted in the presence of a scintillating Trition.

The result is expressed directly as a 50% inhibiting concentration(IC₅₀), (the concentration of the test product, expressed in nM,necessary to displace 50% of the specific radioactivity fixed on thereceptor under study.

Results

The IC₅₀ found was 5.6 naomoles for the product of Example 1 and 5.3nanomoles for the product of Example 7.

B. Anti-arrythmic action in the rat

Male rats weighting 300 to 350 g were tracheotomized after having beenanaestetized intrapertioneally with 1.20 g/kg of urethane and weresubmitted to artifical respiration (40 to 50 insufflations of 3ml/minute).

Needles were implanted sub-cutaneously to register theelectrocardiogramm of the rats on the DII derivation signal.

The test products were administered intravenously and five minutes afterthe administration of the product, the jugular vein of the rats wasprefused with 10 ug/mn from 0.2 ml of an aconitine solution and the timetaken for disturbances of the cardiac rhythm to appear was noted. Theresults are expressed as a percentage of the protraction of the timetaken for disturbances of the cardiac rhythm to appear as compared withcontrols and as a function of the dose of the product tested. Theresults appearing in the Table below show that the product of Example 2was endowed with good anti-arrythmic properties.

    ______________________________________                                                     Dose    Percentage of the protraction of                         Product of Example 2                                                                       mg/kg   time                                                     ______________________________________                                                     10      +43%                                                                  5       +28%                                                                  2.5     +16%                                                     ______________________________________                                    

Various modifications of the products and methods of the invention maybe made without departing from the spirt or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound having a formula selected from the groupconsisting of ##STR6## wherein R₁ is alkyl of 1 to 5 carbon atoms, R₂ ishydrogen or alkyl of 1 to 5 carbon atoms and X is halogen.
 2. A compoundof the formula ##STR7## wherein R₁ is alkyl of 1 to 5 carbon atoms andR₂ is hydrogen or alkyl of 1 to 5 carbon atoms.